Review

Acta Neurol. Belg., 2010, 110, 135-147

Management of cryptogenic stroke

Josef FINSTERER, MD, PhD
Krankenanstalt Rudolfstiftung, Vienna, Austria

Abstract
Cryptogenic stroke(CS) is defined as cerebral ischemia
of obscure or unknown origin. The cause of CS remains
undetermined because the event is transitory or reversible,
investigations did not look for all possible causes, or
because some causes truly remain unknown. One third of
the ischemic strokes is cryptogenic. CS is more frequent
in younger than older patients and most frequently due
to cardiac embolism, followed by vasculopathy, and
coagulopathy. The most frequent causes of cardiac
embolism include paradoxical embolism from upstream
veins via a patent foramen ovale(PFO), paroxysmal
atrial-fibrillation, valvular heart-disease, and atrial septal
aneurysm. The most frequent vascular causes of CS are
complex aortic plaques and Fabrys disease. Diagnostic
work-up for CS includes transesophageal echocardiography, long-term ECG-recordings, CT-/ MR-angiography
of the aorta, transcranial Doppler-sonography, imaging
for venous thrombosis in case of paradoxical embolism,
and blood chemical investigations and coagulation tests.
Recurrence rate and prognosis of CS is under debate.
Primary and secondary stroke prevention in CS is not
at variance from stroke of known cause. If the cause of
CS can be identified, appropriate treatment is indicated.
A PFO requires antiplatelet medication, OAC if there
are other indications for OAC, and closure in case of
recurrent CS under OAC.
Key words: Cryptogenic stroke; stroke of undetermined
cause; cerebral ischemia; pathogenesis, cause of stroke;
patent foramen ovale; paroxysmal atrial fibrillation.

Introduction
The term cryptogenic means that the cause of
a condition is of obscure or unknown origin and
thus remains to be determined. Though the term is
frequently used together with disease, there is no
human disease without a cause, thus no stroke without an aetiology (cryptogenic stroke (CS) (Table 1).

The cause of an ischemic stroke may remain cryptogenic because 1. the event is transitory or reversible
and diagnostic work-up is not carried out in due
time, 2. investigations do not look for all known
causes of stroke, or 3. some causes of stroke truly
remain unknown (1). The rate of CS thus depends
on the definition of the term complete and how
extensive and how rapid the diagnostic work-up
is carried out (Table 2). The likelihood to detect
the cause of a CS, however, increases if methods
beyond routine diagnostic tools (carotid ultrasound,
transthoracic echocardiography (TTE), 24h-Holtermonitoring) are applied. Delineation of CSs from
stroke of undetermined cause is arbitrary why both
terms should be used synonymously (2). As with
strokes of known cause, causes of CS can be classified as cardiac, vascular, hemodynamic, or thrombophilic. CS most frequently occurs in patients
< 55 y of age (juvenile stroke) as compared to stroke
in the elderly, which is most frequently due to atrial
fibrillation (AF) or atherosclerosis (1, 3). This
minireview wants to give a short overview on the
knowledge and most recent findings concerning the
frequency, aetiology, pathogenesis, diagnosis, and
treatment of CS.
Review criteria
The database in which it was searched for appropriate articles was MEDLINE. The period during
which it was searched for appropriate publications
was 1966 to December 2009. The search terms
were cryptogenic stroke, stroke of undetermined
cause, ischemic stroke, and cardioembolic
stroke. The vast majority of the selected papers
were full-text papers written in English. The vast
majority of the papers reported studies on humans
but animal studies were also included if relevant for
the topic. Reference lists of identified papers were
further searched for further leads.

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Table 1

Table 2

Causes of cryptogenic stroke

Diagnostic work-up for CS

Cardiac
Frequent
PFO*
Atrial septal defect*
Atrial septal aneurysm (ASA)*
Atrial fibrillation
Heart valve disease*#
Regional myocardial dyskinesia
Dilated left atrium
Rare
Right atrial Chiari network*
Prominent Eustachian valve* (conducts the blood from
the caval vein directly into the right atrium)
Spontaneous echocontrast within the right atrium*
Ventricular thrombus*
Left atrial appendage thrombi*
Dilative cardiomyopathy*
Restrictive cardiomyopathy*
Takotsubo syndrome*
Left ventricular hypertrabeculation*
Endomyocardial fibrosis
Left atrial bands*
Papillary fibroelastoma*
Atrial myxoma*
Lung
Hereditary teleangiectasia Rendu-Osler
(paradoxical embolism from pulmonary AV-shunts)
Vascular
Atherosclerosis
Large arteries (aortic plaques*), small arteries
Fabrys disease
Aortic dissection*
Mural thrombi over dissected aortic segments*
Coagulopathic
Arterial hypercoagulability
Antiphospholipid antibody syndrome
Elevated lipoprotein (a)
Tissue factor mutation
Hyperhomocysteinemia
Venous hypercoagulability
Inherited
Antithrombin-III deficiency
Protein-S deficiency
Protein-C deficiency
Factor II deficiency
Heparin cofactor II deficiency
Prothrombin mutations
Activated protein C (APC)-resistance
Fibrinolytic system abnormalities (plasminogen or
tissue plasminogen activator deficiency, elevated
plasminogen activator inhibitor)
Hereditary hyperhomocysteinemia
Factor XIII polymorphisms
Acquired
Acquired hyperhomocysteinemia
Neoplasm

Useful
TEE
Long-term ECG-recording
CT- or MR-angiography of the aorta and its thoracic
branches
TCD
Venous ultrasound, MR-venography, phlebography
Ordinary blood investigations
Blood cell count (polycythemia vera, thrombocytosis)
(82), D-dimer, urine protein
Coagulation test
Arterial hypercoagulability (lupus anticoagulant, anticardiolipin antibodies, lipoprotein A, tissue factor mutations, hyperhomocysteinemia)
Venous hypercoagulability (activated-protein-C (APC)resistance, deficiency of protein-C, protein-S, or antithrombin-III, heparin cofactor II deficiency,
prothrombin gene mutations, fibrinolytic system abnormalities (factor XIII polymorphisms), hyperhomocysteinemia (67))
Alpha galactosidase (GLA genetics)
Questionable
3D-MRI
Multidirectional 3D-MRI velocity mapping
FDG-PET
Cardiac MRI
Intracardiac echocardiography
Biological assays

*: detected on TTE or TEE, #: heart valve disease include

thickened valves, mitral prolapse syndrome, aortic valve strands,
aortic valve stenosis, mitral valve strands, mitral valve stenosis,
mitral valve ring calcification, valve thickening, aortic valve
sclerosis, Libman-Sacks endocarditis, marantic endocarditis,
Lambls excrescences

Operational definition
A common binding definition of CS is not available. However, CS is most commonly defined as an
ischemic cerebrovascular event of which the cause
remains undetermined in the absence of smoking, if
arterial hypertension, diabetes, and hyperlipidaemia
are well controlled or absent, and if carotid ultrasound, transthoracic echocardiography (TTE), routine ECG, determination of the thrombocyte count,
alpha-galactosidase, long-term ECG, coagulation
studies, transcranial ultrasound (TCD), or transesophageal echocardiography (TEE), have been
proven normal.
Frequency
Despite a complete work-up the cause of ischemic
stroke remains undetermined in 20-40% of the cases
(1-10). In a study of 130 consecutive stroke patients
with a patent foramen ovale (PFO) the prevalence of
CS was even 67% (11).

CRYPTOGENIC STROKE

Pathogenesis
A. CARDIAC CAUSES
The most common cause of CS is presumably
cardiac embolism. A cardiac cause of embolism can
be eventually detected in at least half of the patients
with CS (4,10). Though there are a large number
of cardiac sources of embolism involved in the
pathogenesis of CS, a few are more prevalent
than others. The most common causes of cardiac
embolism in CS include paradoxical embolism
originating from crural or pelvic veins via a PFO,
atrial septal aneurysm (ASA), paroxysmal AF (pAF),
or valvular heart disease (Table 1). More rare causes
of CS from cardiac embolism are listed in Table 1
(4, 12). Recently, enlargement of the left atrium and
development of AF were proposed as the common
pathomechanism of cardioembolic CS in patients
with a PFO and ASA (13).
1. Patent foramen ovale (PFO)
a) General
The cardiac abnormality most frequently associated with CS is the PFO, particularly in subjects
< 55y (2, 14, 15), although some studies reported an
association between CS and PFO also in patients
> 55y (16-18). A PFO can be detected in 40-50% of
the patients with CS (3, 10, 18-24) but in single studies extreme figures of 22% (4) respectively 88% (25)
have been reported. Investigating 227 patients with
CS, a PFO was found in 43.9% of the young patients
and in 28.3% of the old patients (18). Patients > 65y
of age have a 3 times higher risk to develop a stroke
if a PFO is present (3). PFO is more prevalent in men
than women with CS (26). With only 15-30% of the
normal population having a PFO (24, 27-30) the frequency of PFO is higher in CS patients as compared
to healthy controls (10, 24). In CS patients PFOs are
larger, have longer tunnels, and are more frequently
associated with atrial septal aneurysm (ASA) as
compared to patients with stroke of known cause
(31). Since the source of embolism in the presence
of a PFO is usually not the heart but the upstream
veins, a PFO usually constitutes a risk factor for
CS but not the cause of CS (2). Accordingly, the
association of stroke and PFO is not sufficient to
diagnose paradoxical embolism (32) and investigations of the peripheral veins for thrombosis and
coagulation tests are necessary. Since PFO is a
tunnel-like structure with possibly stagnant flow,
also in situ thrombus formation may occur (24).

137

b. Diagnosis
PFO can be detected with the same accuracy by
TEE as by TCD (23). In case of diagnosing CS and
PFO the upstream particularly crural and pelvic
veins need to be investigated for thrombosis by
Doppler ultrasound, MR-venography, or phlebography immediately after the event. Clinical clues to the
diagnosis of paradoxical embolism include the coexistence of deep venous thrombosis, pulmonary
embolism, migraine, recent prolonged travel, sleep
apnea, waking up with a transitory ischemic attack
(TIA) or stroke, or a Valsalva manoeuvre (32). The
morphological pattern of a PFO may be classified as
simple (central/superior eccentric shunt or with valve
mechanism), reduced (widely redundant septum primum), entire atrial septal aneurysm (EASA), cribriform, or as tunnel between septum primum and
secundum > 10mm (33). Risk factors of paradoxical
embolism in addition to a PFO are the presence of
an ASA, Eustachian valve, or a Chiari network,
which can be best detected by intracardiac echocardiography (34,35). The risk of stroke is particularly
increased in young patients with a PFO (36). The
only prothrombotic marker related to PFO size is the
presence of antiphospholipid antibodies (37).
c. Arguments for a causative role of PFO
There are a number of arguments in favour and
against a contributing role of PFO in CS, why no
final decision can be made with regard to the pathogenicity of a PFO for CS. Arguments in favour
of a causative role are: 1. PFO is more frequent
in CS patients than in the normal population (38).
2. PFO is more frequent in patients with CS than
in stroke patients with known cause. In a study of
130 stroke patients a PFO was found in 41% of the
young and in 25% of the old patients with CS but
only in 14.3% of the patients with a stroke of known
cause (11). 3 In CS patients the presence of a PFO
is associated with a low atherosclerotic burden, as
measured by carotid intima media thickness (21). It
was assumed that in patients with a PFO a nonatherosclerotic mechanism is involved, whereas
in CS patients without a PFO an atherosclerosismediated mechanism prevails (21). 4. The recurrence
rate of CS in patients with a PFO is lower after PFOclosure than in patients without (Table 3) (39, 40).
d. Arguments against a causative role of PFO
Arguments against a contributing role of PFO in
CS are: 1. the recurrence risk of stroke in patients
with a history of CS and PFO is not increased com-

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Table 3
Recurrence rates of CS in patients with or without PFO in various studies
Study

NOP

FUP

RR

RRY

RFR

Palomeras 2009 (6)

121

1y

2.8

2.8

NG

Mas 2001 (50)

581

4y

4.2

1.1

NG

Mas 2001 (only PFO) (50)

581

4y

2.3

0.6

None

Mas 2001 (PFO + ASA) (50)

581

4y

15.2

3.8

Presence of PFO + ASA

Serena 2008 (45)

486

729d

5.8

2.9

None (neither PFO nor ASA)

Van de Wyngaert 2008 (95)#

66

100pat.y 16.6

11.1

NG

Nedelchev 2002 (20)

159

29m

13.4

5.5

Previous stroke

Ford 2009 (92)

150

6y

0.9-2.8

0.2

Increased PP, APC-resistance,

Harrer 2006 (91)

41

10y

NG

2.1-2.9

Large shunts, pulmonary embolism, previous stroke,

ASA no pedictor

Spies 2008 (15)*

423

18m

NG

1.8

NG

Spies 2008 (15)#

423

18m

NG

1.3

NG

Luermans 2008 (48)

83&

0.7-31y

1.2

NG

NG

Van de Wyngaert 2008 (95)#

66

3.73y

None

Ford 2009 (92)

352

6y

0.9-2.8

NG

Increased PP, APC-resistance, protein-S deficiency

Gasiavelis 2004 (96)

33

99m

0.7

NG

No PFO

PFO, no closure

PFO, after closure

NOP: number of included patients, FUP: follow-up period, RR: recurrence rate in percent, RRY: recurrence rate per year in percent,
RFR: risk factors for recurrence, NG: not given, PP: pulmonary pressure, *: patients >55y, #: patients <55y, & only 59% had a CS

pared to those without a PFO (41). 2. about one third

of the patients with CS and PFO would not profit
from closure of the PFO (14). 3. the lesion pattern
on cerebral MRI is not at variance in patients with
PFO and CS as compared to those with CS but without a PFO (42). 4. the risk of stroke is not increased
in patients with a PFO alone or a PFO with ASA
as compared to controls (29). 5. the combined presence of PFO and anti-phospholipid syndrome does
not increase the risk of subsequent cerebrovascular
events in patients with previous CS (43). 6. right-toleft shunt is no independent risk factor for stroke in
patients with CS (22). 7. the prevalence of prothrombin mutations is higher in patients with a PFO
as compared to stroke patients without a PFO (44).
8. neither PFO nor ASA are independent risk factors
for recurrence of stroke in CS patients (45).
2. Atrial septal aneurysm (ASA)
The definition of ASA is under debate but most
frequently it is defined as > 10mm excursion of the
intra-atrial septum and affects ~2% of the general
population (30, 46). An ASA can be detected in up
to 50% of the cases with a PFO. ASA is independ-

ently associated with ischemic cerebral events possibly interacting with thrombophilia (20, 47,48), In
some studies stroke recurrence is particularly increased if both PFO and ASA are present (Table 3)
(49,50). Generally, the association between CS and
ASA with PFO is independent of age (18). ASA is
usually associated with a large PFO, prominent
Eustachian valve, or prominent right atrial filamentous strands (51). In a study of 121 patients with CS,
ASA was present in 24% of them (19).
3. Intermittent or paroxysmal AF (pAF)
AF is the most common cause of embolic stroke
in industrialized countries (52,53). AF may be classified as permanent, intermittent or paroxysmal (pAF).
pAF is assumed to play also a dominant role in the
pathogenesis of CS. It is speculated that in a number
of patients CS is due to intermittent or pAF (7). In a
study of 121 CS patients pAF was recorded on standard ECG in 6.4% during a one-year follow-up (6).
The longer and the more intensively it is searched
for pAF, the more likely it is detected. If pAF cannot
be detected by standard ECG, 24h-Holter, 48hHolter, 7d-Holter, or telemetry, it may be detected

CRYPTOGENIC STROKE

139

Table 4
Treament options for stroke prevention in patients with CS (30)
Abnormality

Treatment

PFO alone

APM

PFO + AF or SD

OAC

PFO + AF or SD but CI for OAC

PFO-closure

PFO and recurrent CS under OAC

PFO-closure

PFO + ASA

OAC

AF, pAF, atrial flutter

OAC

Aortic plaques

APM, statins, OAC if there is AF or SD

Arterial dissection (extracranial)

OAC for 3-6 months

Arterial dissection + recurrent CS

Stenting

Thrombophilia + thrombosis + CS

OAC

APLABS (only antibodies) + CS

APM

APLABS (clinical manifestations) + CS

OAC

Fabry

Enzyme replacement therapy

PFO: patent forame ovale, APM: antiplatelet medication, OAC: oral anticoagulation, AF: atrial fibrillation,
APLABS: antiphospholipid antibody syndrome, SD: systolic dysfunction, CI: contra-indication

by an event recorder or by loop recording. pAF may

be indirectly predicted by application of the STAF
score. If the score exceeds a value of 5, pAF is quite
likely (53). Items, which constitute the STAF score
include age > 62y (2 points), NIHSS 1, atrial dilation (2 points), absence of intra- or extra-cranial
atrial stenosis > 50%, or a clinical or radiological
lacunar syndrome (3 points) (53).

(e.g. vertebral artery origin stenosis), the intracranial

arteries (e.g. middle cerebral artery stenosis), or the
small intraparenchymatous arteries may be affected
(55). Atherosclerosis is usually progressive resulting
in narrowing of the luminar diameter, stenosis,
occlusion, or mural thrombus formation with consecutive arterial embolism (56).
1. Atherosclerosis

4. Valvular heart disease

In a study of 702 patients with CS valvular abnormalities were the second most frequent echocardiographic abnormality, found in 15.8% of the cases (4).
Aortic valve sclerosis was found in 9.4%, mitral prolapse syndrome in 2.1%, aortic valve strands in
0.9%, aortic valve stenosis in 0.7%, mitral valve
strands in 0.7%, and mitral valve stenosis in 0.14%
of the cases (4). More rare valve abnormalities associated with CS are listed in Table 1 (54). Valve thickening may be an indicator of an anti-phospholipid
antibody syndrome (43).
B. VASCULAR CAUSES
The most frequent types of vasculopathy associated with CS are atherosclerosis and arteriopathy
from Fabrys disease. Atherosclerosis affects all
sizes of arteries (small, medium-sized, large arteries)
why the proximal cardiac arteries (e.g. complex
plaques in the aortic arch), the extra-cranial arteries

Aortic plaques
Complex aortic plaques or complex atheroma (i.e.
plaques with attached thrombus) upstream to the left
subclavian artery or the right truncus brachiocephalicus constitute a frequent pathomechanism of CS (2).
How often embolism from complex aortic plaques
is responsible for CS is unknown but it is estimated
that up to one fifth of the CSs are due to embolism
from aortic plaques. Aortic plaques are frequently
found in patients with CS > 60y (2). Among patients
with embolic events, aortic atheromas are found in
about one quarter of them (57). Aortic plaques can
be visualized by TEE, CT- or MR-angiography, or
multidirectional 3D-MRI (58). In a subgroup analysis of 40 patients with CS, plaques in the aortic arch
were detected by CT-angiography in 20.5% of them
(8). With 3D-MRI the aortic arch can be investigated
with high accuracy and complex plaques can be most
effectively visualized (58). 3D-MRI provides exact
plaque localization and can be combined with multidirectional 3D-MRI velocity mapping (58). There

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are some indications that the risk of stroke is increased only if the thickness of a plaque is > 4 mm
(2, 59). In single cases, dissection of the aorta with
a mural thrombus may lead to cerebral embolism
(9, 55, 60). In a study of 26 patients with CS aortic
dissection was detected on 3D-MRI in two of them
and 6 others had plaques > 4mm (61).
Small- and medium-sized arteries
Frequently, atherosclerosis and stenosis of the
medium- or small-sized intra-cerebral arteries
remain unrecognized in CS. Meanwhile, however,
previously undetected abnormalities may be
detectable by high-resolution MRI. An argument
for atherosclerosis to play a pathogenetic role in the
development of CS is that moderate stenoses of the
carotid artery are more frequently found in patients
with CS than in patients with stroke of definite cause
(2). Intracranial stenosis may be detected upon MRangiography or by TCD.
2. Arteriopathy from Fabrys disease
Fabrys disease is an X-linked recessive lysosomal storage disease resulting from deficient alphagalactosidase and leading to accumulation of
glyco-sphingolipids and storage of the material in
the vascular endothelium with consecutive microand macroangiopathy and enlargement of the arteries
(62, 63). In a study of 721 patients with CS, mutations in the alpha-GAL gene were found in 4.9% of
the male patients and in 2.4% of the female patients
with CS (62). The disease manifested clinically in
1.2% of all patients and was more frequent in the
vertebro-basilary artery system than in the anterior
circulation (62). This explains why these patients had
an increased frequency of dolichoectatic pathology
of the basilary artery (62, 63). The figures about the
prevalence of Fabrys disease in CS have been
recently challenged.
C. COAGULOPATHIES
In a small number of CS patients inherited or acquired hypercoagulability can be found if systematically looked for (64, 65). Generally, coagulopathies
may be classified according to the preferentially
affected vascular bed into venous or arterial hypercoagulability or according to the pathogenesis into
hereditary or acquired forms.
Arterial hypercoagulability
The most frequent condition associated with
arterial hypercoagulability is the antiphospholipid

antibody syndrome (66). The antiphospholipid antibody syndrome is an acquired form of arterial and
venous hypercoagulability associated with thrombocytopenia, livedo reticularis, and increased frequency
of pregnancy-related complications, such as miscarriage, stillbirth, abortions. or preeclampsia. The syndrome is due to the production of autoimmune
antibodies against phospholipids, cardiolipin, or
beta-glycoprotein I. The condition is diagnosed upon
the clinical presentation and the presence of antiphospholipid and anti-cardiolipin antibodies (67).
More rare causes of arterial hypercoagulability with
increased risk of cerebrovascular ischemic events,
include the acquired hyperhomocysteinemia, the
tissue factor polymorphism + 5466A> G (66), and
high lipoprotein A (68).
Venous hypercoagulability
Inherited and acquired disorders with venous hypercoagulability are listed in Table 1 (65). Whether
any of these hypercoagulabilities is indeed associated with CS is so far unknown. In a recent study of
167 patients with ischemic stroke, prothrombin and
factor XIII polymorphisms were not associated with
any thromboembolic event but the prevalence of the
Leyden mutation was increased (64). A study of
89 patients with stroke and PFO showed that also
altered fibrin clot structure and resistance to fibrinolysis are associated with CS (69).
Diagnostic work-up
Patients with CS need to undergo a number of investigations to eventually find the cause of CS. The
most important of these investigations are TEE,
long-term ECG recording, MR- or CT-angiography
of the aorta, TCD, search for upstream venous
thrombi by venous ultrasound, MR-angiography, or
phlebography in case of a PFO, and blood investigations, including investigations for hypercoagulability
(Table 2).
Transesophageal echocardiography (TEE)
TEE is indicated in CS patients if TTE is nondiagnostic (61, 70). TEE detects relevant abnormalities in about half of the young patients with CS (4,
71), although figures up to 100% have been reported
(61). Relevant findings in patients with CS include
PFO (22-29%) with spontaneous or provocable (Valsalva manoeuvre) right-to-left shunt after application
of contrast medium or a bubble test (4), previously
undetected valve disease (16%) (4), ASAs (1%),
aortic plaques, regional myocardial dyskinesia, or

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dilated left atrium (Table 1) (4). TEE may also reveal

more rare sources of embolism as listed in Table 1.
In a study of 231 consecutive CS patients TEE detected a major cardiac risk factor with indication for
OAC in 16% of the cases (72). Some authors preferentially recommend TCD instead of TEE for PFO
detection in patients with CS since the concordance
of recognition is high and since TCD is more simple
and non-invasive (23). Generally, TEE findings may
change the treatment in about one third of the CS
patients (61). In a retrospective study of 54 patients
with CS TEE findings changed the management in
1 out of 3 patients (73). In a study of 100 patients
with CS, however, TEE changed the management
even in 90% of the patients with abnormal TEE and
suggested PFO closure in 38 of them, surgery in
three patients, and OAC in five patients (71).

dissection are suspected (60). Available techniques

include multi-detector CT (52), high-resolution
MRI, 3D-MRI, multidirectional 3D-MRI, or FDGPET. In a study of 26 CS patients 3D-MRI identified
aortic high risk pathologies in 8 patients. In two
patients aortic dissection and in 6 cases plaques
with a thickness of > 4 mm were found (61). Multidirectional 3D-MRI velocity mapping is a new
method, which allows the demonstration of retrograde flow paths originating from complex plaques
of the descending aorta resulting in a potential
hemodynamic stroke mechanism (58). FDG-PET
may be useful to detect plaques in the carotid artery
(2). Noninvasive FDG-PET has a complementary
value for the evaluation of atherosclerotic plaque
composition and activity since lipid-rich plaques are
more inflamed than calcified or collagen-rich
plaques (81).

Long-term ECG recording

Long-term ECG recording is strongly recommended in CS patients, particularly when they report
palpitations, when the morphological stroke-pattern
on MRI suggests an embolic cause (7), or when there
is enlargement of the left atrium (STAF score). The
longer the period, during which an ECG is recorded,
the more likely a relevant rhythm abnormality may
be detected. Long-term ECG recording may be particularly helpful to detect pAF. Long-term ECG
recording can be carried out by 24h-, 48h-, 7dHolter, mobile cardiac outpatient telemetry, event
recorders (allow up to 30d ECG-monitoring), or
loop-recorders (recording up to 2y) (2, 7, 74). 24- or
48h Holter monitoring detects new onset AF in 1-5%
of the stroke patients (75, 76). If Holter-monitoring
is extended to 7d, occult AF may be detected in up
to 26% of the CS patients (77). The rate of newlydiagnosed pAF during inpatient cardiac monitoring
by telemetry ranged between 4-8.4% (78). In a study
of 56 patients with CS pAF could be detected in 23%
by 21d mobile outpatient telemetry (74). In a study
of 60 stroke patients 6.7% showed pAF upon eventrecording during an average of 70h, of which
one third went undetected by conventional ECG
or ordinary Holter-monitoring (79). In a study of
36 patients with CS 20 patients were evaluated by
means of a 30d-event recorder and in 20% of them
pAF was recorded (7). In a study of 149 stroke
patients new-generation event recorders detected
pAF in 5.7% of them (80).
MR- or CT-angiography and FDG-PET
MR- or CT-angiography should be carried out in
patients in whom complex aortic plaques or aortic

Detection of venous thrombosis

If there are indications of paradoxical embolism
or deep venous thrombosis or thrombosis of the
more proximal veins, search for venous thrombi by
means of a Doppler ultrasound of the crural veins,
MR-venography, or even phlebography needs to
be carried out. One problem with determining the
cause of CS is that mobile intracardiac or luminal
thrombi may have disappeared at the time of the
investigation (55).
Blood investigations
If venous thrombosis with paradoxical embolism
or sinus venous thrombosis are suspected, determination of the D-dimer may be helpful. If Fabrys disease is suspected, the urine should be investigated
for increased protein and for serum levels of alphagalactosidase (62). If the alpha-galactosidase is
reduced the GLA gene should be sequenced for point
mutations or screened for deletions by MLPA. If an
anti-phospholipid antibody syndrome is suspected
the thrombocyte count, the lupus anticoagulant, and
the anti-cardiolipin antibodies should be determined
(43). Concerning the search for hypercoagulability,
there is no consensus about the usefulness of such
investigations. Since there is a lack of studies comparing OAC with anti-platelet therapy in patients
with CS and thrombophilia, laboratory screening for
thrombophilia remains of questionable value in CS
patients (65). Other groups, however, recommend to
individualize the decision on the therapeutic consequences and to screen for arterial and venous hypercoagulability (82).

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Treatment
Drug treatment
OAC for secondary prevention of stroke is indicated if there is pAF (52), if the morphological
stroke pattern suggests an embolic cause, or in case
of intracardiac thrombus formation (83). If OAC is
given in these indications it reduces the risk of recurrent stroke by 2-8% per year (3). Whether OAC
is indicated for primary or secondary prevention of
stroke in patients with a PFO is unsolved (10, 35,
84). Among 576 patients treated with acetyl-salicylic
acid (ASS) or OAC the recurrence risk of cardioembolic events was similar in both groups (85). There
was also no difference between the two treatments
concerning the prevention of death or the rate of
major bleedings (85). When comparing event rates
between patients under ASS and under OAC there
was no significant difference (21). In another study,
however, the 2y rate of stroke recurrence or death
was lower in patients receiving OAC than in patients
receiving antiplatetelet medication (86). According
to recent guidelines OAC is reasonable for high-risk
patients only if they have other indications for OAC
(30). In the majority of the cases antiplatelet treatment is reasonable to prevent a recurrent event (30).
The best medical treatment of patients with CS or
PFO plus ASA is OAC (10). Whether OAC is also
superior to antiplatelet drugs in patients with antiphospholipid syndrome is under debate (65). There
is no consensus on antiplatelet drugs vs. OAC for
secondary stroke prevention according to a study
of 519 patients with severe aortic plaques of whom
111 experienced an embolic event (87). Statins have
been proven beneficial in complex aortic atheroma.
Patent foramen ovale closure
Though PFO-closure by percutaneous devices or
open surgical repair suggests to be an alternative or
additive to medical therapy with antiplatelet agents
or OAC for secondary prevention of CS, it is under
debate if a PFO in a CS patient should be closed at
all or if such a patient should receive other treatment
(10, 88, 89). According to recent guidelines PFO closure is indicated only in patients with recurrent CS
caused by presumed paradoxical embolism through
a PFO who have failed therapeutic dosages of OAC
(24, 30, 89). Closure may be also considered if MRI
suggests multiple or recurrent CSs or when the onset
of CS is associated with elevation of right atrial pressure (30, 89). Further arguments for closure of a PFO
are that in single cases OAC are contra-indicated
(90) and that there are studies favouring closure
when comparing outcome and recurrence rates of CS

in patients with PFO treated with antiplatelet agents,

OAC, or PFO closure (Table 3) (19,45). Arguments
against PFO closure are that recurrence rates of CS
between patients with and without PFO treated with
warfarin or ASS did not differ (PICSS study) (86),
that recurrence rates of CS were not different between the medically treated and the closure group
(91), and that closure also carries a procedural risk
and does not prevent recurrence of embolic events
in each case (92). Before closure of a PFO in a
patient with CS, however, other potential causes of
CS, such as arterial or venous hypercoagulability
have to be carefully ruled out not to expose the
patient against a procedural risk without minimizing
the risk of stroke recurrence (93).
Prognosis
There are only limited data concerning the prognosis of CS available. Most data about the prognosis
of patients with CS have been collected during studies of patients after PFO-closure. Studies on this
matter, however, are difficult to compare because of
non-uniform inclusion criteria, for varying definitions of CS and TIA, because of variable age, selection bias, for absent blinded adjudication of events,
for a prolonged period between index event and closure, and for insufficient account of medical treatment in patients undergoing closure in some studies
(24). Generally, the prognosis of CS is dependent on
the size of the stroke, the degree of disability resulting from CS, and the management of the underlying
cause. Whether recurrence rates are different
between CS patients with and without a PFO and if
an ASA in CS patients with a PFO increases the risk
of recurrence is under debate (24). Some studies
showed that the risk of recurrence is increased in the
presence of a PFO, whereas other studies found that
an unclosed PFO does not increase the recurrence
risk of stroke (Table 3). Recurrence of CS in patients
without a PFO ranges between 1.1 and 2.8%. per
year (Table 3) (6, 50). In a study of 943 patients
being either on ASS or OAC the annual stroke rate
was 1.98% (24). Some studies showed that the
recurrence risk is significantly increased in the presence of an ASA (30, 50), whereas others did not confirm these results (Table 3) (40, 91). In CS patients
with an untreated PFO recurrence rates of stroke
range between 0.2 and 11.1% per year (Table 3).
According to a number of studies (50,94) the risk of
stroke recurrence in patients with a medically treated
PFO increases with the time after the index event
(10). CS patients with a closed PFO have a recurrence rate of 0-7.8% per year (Table 3) (94). Except
for two studies the recurrence rate of CS is similar

CRYPTOGENIC STROKE

in patients with untreated PFO and in patients

with a closed PFO (Table 3). Whether the rate of
recurrence or adverse outcome is different between
CS and stroke of determined cause is unsolved.
Some studies report a higher rate of recurrence in
CS (1) whereas others show the opposite.
Conclusions
To determine the cause of CS at the moment,
patients should, in addition to routine diagnostic
work-up (carotid ultrasound, TTE, 24h-Holtermonitoring), undergo TEE to look for a PFO or other
cardiac sources of embolism, long-term ECG recording to detect pAF or atrial flutter, CT- or MRIangiography of the proximal aorta to detect aortic
plaques with mural thrombi or aortic dissection,
TCD to look for intracranial artery stenosis, imaging
for venous thrombosis in case of paradoxical embolism, or blood chemical investigations or coagulation
studies to look for arterial or venous coagulopathy,
anti-phospholipid antibody syndrome, or Fabrys
disease. To increase the accuracy of TTE and to
lower the high inter-observer variability clear-cut criteria for the diagnosis of PFO and ASA have to be
provided. Additionally, national and international
neurological and rehabilitational societies are asked
to clearly define CS, determine which tools routine
and additional diagnostic work-up should include,
at which point further diagnostic measures are
indicated, and to recommend an algorithm for the
diagnostic work-up of CS. To provide convincing
evidence with regard to available and upcoming
treatment options, more randomised, controlled studies are needed. In the upcoming years, new diagnostic tools may hopefully determine, which pathologies
are definitively causally related to CS and welldesigned therapeutic trials may provide evidence for
the optimal management of these conditions.
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J. Finsterer, M.D., PhD

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